Chronic obstructive pulmonary disease (COPD) affects 15 million patients in the U.S. and is the sixth leading cause of death. It is characterized by the retention of mucus secretions in the lungs. Many patients diagnosed with COPD have a disorder called chronic bronchitis (CB), and 600,000 patients are hospitalized each year due to an acute exacerbation of CB. Cystic fibrosis and Primary Ciliary Dyskinesia (PCD) are other examples of lung disorders which assume a clinical profile similar to COPD. Ciliary dyskinesia, whether primary or secondary, results in retained secretions that can only be cleared by coughing.
Another disease state characterized by the accumulation of retained mucous secretions is sinusitis, an inflammation of the paranasal sinuses typically associated with an upper respiratory infection. Sinusitis is this country's most common health-care complaint, affecting an estimated 31 million people. (A. Moss and V. Parsons, National Center for Health Statistics, 1986: 66-7, DHHS Publication No. (PHS)86-1588 (1985)).
Otitis media (OM) is a viral or bacterial infection of the middle ear, which primarily afflicts children under the age of three years. It is usually precipitated by an upper respiratory infection which spreads into the middle ear via the nasopharynx and eustachian tube. Approximately 25-50 million office visits are made each year for diagnosis and treatment of OM. By age three, about 75% of children will have had at least one episode of acute OM (J. Klein, Clin. Infect. Dis. 19, 823-33 (1994)). Following appropriate treatment with antibiotics, accumulated fluid in the middle ear remains, causing hearing impairment and potential language and cognitive development delays. Enhanced ability to clear secretions in the middle ear would reduce or eliminate significant sequelae of otitis media.
An additional disorder resulting from retained secretions is pneumonia. Patients who are immobilized for a variety of reasons are at high risk for developing pneumonia. Despite extra vigilance and numerous interventions, pneumonia develops in over 400,000 patients per year, with significant morbidity and mortality.
Mucous secretions are normally removed via the mucociliary clearance (MCC) system. MCC relies on the integrated action of three components: 1) mucus secretion by goblet cells and submucosal glands; 2) the movement of cilia on epithelial cells which propels the mucus across the luminal surface; and 3) ion transport into and out of luminal epithelial cells which concomitantly controls the flow of water into the mucus.
Similarly, disorders of secretion may lead to improper hydration at various body sites, thereby resulting in pathological conditions. These include dry eye disease, nasolacrimal duct obstruction, retinal detachment, glaucoma or ocular hypertension, retinal edema, retinal degeneration, improper joint lubrication, inflammatory diseases, vaginal dryness, gastroesophageal reflux, dry mouth, and constipation.
Enhancement of mucociliary clearance or balanced tissue hydration and fluid secretion would thus be useful in the prevention, management and treatment of such disorders. Furthermore, enhancement of mucociliary clearance would also have diagnostic applications such as sputum induction and detection of lung cancer.
It is now known that P2Y receptor agonists modulate many components of the MCC system by: (1) increasing both the rate and total amount of mucin secretion by goblet cells in vitro (Lethem, et al., Am. J. Respir. Cell. Mol. Biol. 9, 315-22 (1993)); (2) increasing cilia beat frequency in human airway epithelial cells in vitro (Drutz, et al., Drug Dev. Res. 37(3), 185 (1996)); (3) increasing Cl− secretion, hence, water secretion from airway epithelial cells in vitro (Mason, et al., Br. J. Pharmacol. 103, 1649-1656 (1991); and (4) releasing surfactant from Type II alveolar cells (Gobran, Am. J. Physiol. 267, L625-L633 (1994)). In addition to such actions, P2Y agonists have also been shown to increase intracellular Ca++ due to stimulation of phospholipase C by the P2Y2 receptor (Brown, et al., Mol. Pharmacol. 40, 648-655 (1991); Yerxa and Johnson, Drugs of the Future 24(7): 759-769 (1999)). U.S. Pat. Nos. 5,789,391; 5,763,447; 5,635,160; 5,935,555; 5,656,256; 5,628,984; 5,902,567; 5,292,498; 5,837,861; 5,900,407; 5,972,904; 5,981,506; 5,958,897; 5,968,913; 6,022,527; 6,133,247; and 6,143,279, and PCT International Patents WO97/29756, WO97/35591, WO96/40059, WO97/05195, WO94/08593, WO98/19685, WO98/15835, WO98/03182, WO98/03177, WO98/34942, WO98/34593, WO99/09998, WO99/32085, WO99/61012, WO 00/30629, WO 00/50024, and WO96/40059 disclose beneficial therapeutic effects of certain dinucleotides and related compounds in sinusitis, otitis media, ciliary dyskinesia, pneumonia associated with immobilization, lung disease, cystic fibrosis, dry eye disease, vaginal dryness, bronchitis, edematous retinal disorders, retinal degeneration and detachment, and gastrointestinal disease. These and all other U.S. patents cited and herein are specifically incorporated herein by reference in their entirety.
Dinucleotides in the prior art are disclosed in the following references (International Patent Nos. WO96/40059, WO96/02554A1, WO-A-9815563, and WO98/55494; Theoclitou, et al., J. Chem. Soc. Perkin Trans. I, 2009-2019 (1996); Guranowski, et al., Nucleosides and Nucleotides 14, 731-734 (1995); Visscher, et al., Nucleic Acids Research 20, 5749-5752 (1992); Holler, et al., Biochemistry 22, 4924-4933 (1983); Orr, et al., Biochem. Pharmacol. 673-677 (1988); Plateau, et al., Biochemistry 24, 914-922 (1985); Hagmeier, et al., J. Chromatography 237, 174-177 (1982); Scheffzek, et al., Biochemistry 35, 9716-9727 (1996); Stridh, et al., Antiviral Res., 97-105 (1981); Tarasova, et al., Chem. Abs. 110, 154770 (1988); Hata, et al., Chem Lett., 987-990 (1976); Huhn, et al., 28, 1959-1970 (1993); Tumanov, et al., Chem. Abs. 109-6867d (1987); Pintor, et al., Molecular Pharmacology 51, 277-284 (1997); and U.S. Pat. Nos. 4,855,304; 5,635,160; 5,495,550; and 5,681,823).
Applicants have discovered new dinucleoside compounds and analogues which are effective in clearing retained mucous secretions, balancing tissue hydration and fluid secretion, and/or inhibiting or preventing early stages of platelet activation, platelet degranulation, and platelet aggregation.